Newly Discovered Blood Marker Could Allow Celiac Blood Test

Researchers at a biotech company discovered that a molecule becomes elevated within hours of gluten consumption.

Diagnosing celiac disease can be a tricky business. Many people who suspect they have the condition may already be refraining from eating gluten at the time of their diagnosis, which makes detecting the inflammation caused by gluten exposure much harder. Under current guidelines, they’re asked to eat gluten regularly for several weeks — with all the unpleasant symptoms that occur as a result, such as bloating, diarrhea, and vomiting — before having a biopsy of their small intestine to inspect for damage.

But the days of this drawn-out, often painful, invasive diagnostic procedure may be numbered, thanks to a new discovery by researchers at a biotech company. It could lead to a blood test that requires only one meal containing gluten to accurately diagnose celiac disease.

In an article published in the journal Scientific Advances, researchers at Massachusetts-based ImmusanT Inc. describe how they discovered a molecule in the blood — known as interleukin-2 (IL-2) — that becomes elevated within hours of gluten exposure in people with celiac disease.

Like many scientific discoveries, this one was something of an accident, with the researchers noticing elevated levels of IL-2 while testing a potential celiac disease treatment involving gluten peptide injections. They followed up with studies of actual people with celiac disease and found the same elevated levels of IL-2 within as little as 2 hours after consuming 3 to 5.7 grams of gluten — about a quarter to half of the average daily gluten intake in the United States.

The researchers write that their discovery of elevated IL-2 “provides definitive evidence of rapid immune activation within 2 hours after administering gluten peptides in almost all” people with celiac disease. They also note that higher levels of IL-2 were associated with an increase in nausea and vomiting in study participants, which may explain how gluten exposure has this effect on some people with celiac disease.

Work is already underway to develop a blood test for IL-2 that can be used in a protocol to diagnose celiac disease. Under such a protocol, someone might get a test for IL-2, eat a meal containing gluten, and then get another IL-2 test a few hours later. Exactly how elevated IL-2 would need to be to diagnose celiac disease remains to be determined.

Stress in Early Life Linked to Celiac Disease in Adults

Certain traumatic events in childhood may increase the risk of developing celiac disease, a new study suggests.

For years, researchers have been teasing out all of the potential factors — both genetic and environmental — that may contribute to the development of celiac disease.

Click here to learn more about celiac disease.

It’s well known that some people are genetically at higher risk for the condition, but not everyone in this category actually develops the disease. No matters what your genetic risk level is, it takes some combination of life events — from gluten exposure to stress on your immune system — to activate the autoimmune attack that defines celiac disease.

Now, researchers at McMaster University in Canada have identified a factor in celiac disease that hasn’t been explored in studies before: trauma during childhood.

They presented their findings at the 2019 Canadian Digestive Diseases Week in Banff, Alberta.

There were 44 adult participants in the study, including 25 people with celiac disease and 19 members of a control group with a similar balance of age and sex as the celiac group. Each participant completed a questionnaire on adverse events in early childhood, as well as one on current digestive symptoms.

The researchers found that people with celiac disease reported significantly more adverse events during childhood than those in the control group. The most commonly reported events were substance abuse in family members and neglectful parenting. 

On average, people in the celiac disease group reported 7 early adverse events, while those in the control group reported only 3.

When looking at a possible link between childhood trauma and current digestive symptoms, though, the researchers found only a weak connection. There was a moderate connection between early adverse events and current severity of constipation. But no connection was found between childhood trauma and current diarrhea, abdominal pain or celiac symptoms outside the digestive tract.

The researchers noted that these results suggest a link between trauma during childhood and later develop celiac disease, although more research is needed to understand the mechanisms involved. The findings also show that people who are diagnosed with celiac disease might benefit from a psychological assessment to help their doctors learn about any trauma that contributes to symptoms.

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Celiac Disease Foundation Announces Young Investigator Research Grants

Last month at the 2019 Digestive Disease Week conference in San Diego, the Celiac Disease Foundation — the leading advocacy and research organization for celiac disease in the United States — announced the two recipients of its 2019 Young Investigator Research Grant Award.

This award is given to younger researchers who are undertaking innovative, promising work related to celiac disease. It’s intended to give a boost not just to the research itself, but to the profile of both the researcher and the project — signaling the ways in which celiac disease treatment and management may be heading.

Here’s an overview of what this year’s recipients, Benjamin Lebwohl, MD, and Jocelyn Silvester, MD, are doing with their research grants.

Exploring gluten exposure and symptoms

Celiac Disease Foundation Announces Young Investigator Research GrantsLebwohl, a gastroenterologist who is director of research at the Celiac Disease Center at Columbia University in New York City, has been awarded $145,650 to support a project studying the link between gluten exposure and subsequent symptoms.

“When people with celiac disease accidentally eat gluten some feel extremely ill, some feel no symptoms, and most people feel something in between,” says Lebwohl. “We are testing the theory that it is the intestinal microbiome — the communities of bacteria that live inside us — that affect the relationship between gluten exposure and symptoms.”

The core of the project involves collecting specimens of gut bacteria from people with celiac disease before, during, and after gluten exposure, then analyzing the composition of the bacteria.

Lebwohl calls the wide variety in reactions to gluten exposure “one of the abiding mysteries in celiac disease,” and hopes to make this phenomenon just a bit less mysterious. By figuring out why certain people react the way they do, he says, it may be possible to develop new strategies to prevent symptoms after exposure.

“This project addresses one piece of the puzzle” that celiac disease represents, says Lebwohl — “namely, the limitations of the gluten-free diet and the fact that nearly everyone gets exposed to gluten at some point.”

Potential new ways to diagnose celiac disease

Celiac Disease Foundation Announces Young Investigator Research GrantsSilvester, a gastroenterologist at Boston Children’s Hospital and instructor of pediatrics at Harvard Medical School, has been awarded $180,000 to study whether a new blood test could help diagnose celiac disease in children.

The new test detects immune cells in the blood, known as T cells, that recognize gluten — indicating that they may be part of an immune system attack related to gluten exposure.

”Right now, available tests for celiac disease work best on patients who are eating gluten,” says Silvester. “Many people who stop eating gluten before seeing their doctor are told to go back to eating gluten for a period of time,” which can lead to unpleasant symptoms and intestinal damage — all in the name of an accurate diagnosis.

Silvester’s project investigates whether the new test can measure T cells activated by gluten in children who are already following a gluten-free diet. It will also explore how celiac disease develops by looking at the presence of these T cells in children with “potential celiac disease,” meaning that they have antibodies (immune system proteins) that suggest celiac disease but normal results from a small intestine biopsy.

”We hope this new blood test will provide a way to diagnose celiac disease in patients who are already on a gluten-free diet,” says Silvester. “This has the potential to revolutionize how patients are diagnosed, and may mean that gluten challenges and intestinal biopsies are no longer needed for many patients.”

New Method Reduces Toxicity of Gluten for People With Celiac Disease

A team of Spanish and Portuguese researchers has developed a method to modify gluten with the aim of reducing its toxicity in people with celiac disease. Researchers hope the method will one day allow people with celiac disease to eat wheat-based foods.

What’s more, they found that in controlled baking tests, the modified wheat flour they created behaved similarly to regular wheat flour — demonstrating that it may be possible someday to create wheat-based products for people with celiac disease.

Reorganizing gluten proteins

To create a form of gluten that’s less toxic for people with celiac disease, researchers at Universidad Politécnica de Madrid (UPM) in Spain and Universidade de Trás-os-Montes e Alto Douro (UTAD) in Portugal produced a reaction using a compound called chitosan, which is an edible polysaccharide. The two molecules — gluten and chitosan — formed what the researchers call “mechanically interlocked supramolecular assemblies,” making the gluten less prone to digestion and exposure to intestinal cells, according to a UPM press release.

In a study published in the journal Molecular Nutrition & Food Research, the researchers exposed intestinal cells derived from people with celiac disease to the new formation of gluten and chitosan. They found that two markers of an inflammatory response to gluten were lower in this situation than when the cells were exposed to traditional gluten molecules.

“We do not remove the gluten proteins” to create the chemical structure used in the experiment, explains Marta Rodríguez-Quijano, a member of the research team at UPM. “We modify them minimally to avoid the toxicity of gluten for these people.”

Dough of the future?

In a separate study published in the journal Food Hydrocolloids, the researchers demonstrated that the gluten-chitosan complex could be used to make bread with visual and textural properties similar to bread made from traditional wheat flour.

The research team hopes that their finding will help trigger a shift in how products suitable for people with celiac disease are developed — away from alternative flours designed to mimic the properties of wheat flour, and toward actual wheat flour that can be made safe for people with celiac disease.

“We believe this research project will allow developing wheat-based products with sensory, nutritional and technological properties similar to traditional products, but safe for people suffering from celiac disease,” says Rodríguez-Quijano.

Gastrointestinal Problems and Mental Health Risk Linked to Adversity in Early Life

In a new study, researchers led by a team at Columbia University have found that emotional deprivation early in life is tied to a higher rate of gastrointestinal problems, along with disruption of the gut microbiome and patterns of brain activity that may indicate a higher mental health risk.

These findings are among the first in humans to show a link between emotional trauma, gut bacteria, gastrointestinal issues and brain activity.

They also mean, according to one of the study’s senior authors, that gastrointestinal problems in children may indicate a higher risk for future mental health problems.

Study compared foreign adoptees with other children

The study, published on March 29, 2019, in the journal Development and Psychopathology, compared 115 children adopted from orphanages or foster care in foreign countries before age 2 with 229 children raised by at least one biologically related caregiver.

As noted in a Columbia University press release on the study, the adoptees all endured an extended period early in life separated from any parental figure, which is known to be a strong predictor of mental health problems in humans. Similar treatment in rodents has been shown to trigger fear and anxiety and harm neurological development.

In the current study, the adoptee group had higher rates of gastrointestinal symptoms like stomach aches, nausea, vomiting, and constipation. The researchers also closely examined a smaller group of 16 children — half of them adoptees and half raised by their biological parents — by collecting stool samples, behavioral information, and brain images.

The researchers found a number of patterns in the data collected from this smaller group. One result is that the adoptees had a distinctly different makeup of their gut bacteria, with less diversity in these microorganisms. Brain activity patterns were correlated with the makeup of gut bacteria, and showed a potentially greater risk of mental health issues in children who were already shown to be at greater risk for gastrointestinal issues.

Implications for mental health screening

The researchers note that while their study couldn’t determine a cause-and-effect relationship among the associations it found, it’s further evidence that gut health and brain health are closely related.

Moreover, the study suggests that “adversity-associated changes in the gut microbiome are related to brain function, including differences in the regions of the brain associated with emotional processing,” according to Nim Tottenham, a professor of psychology at Columbia and senior author of the study. This means, she says, that “gastrointestinal symptoms in young children could be a red flag for future emotional health problems.”

The researchers note that certain animal studies suggest it may be possible to manipulate the gut microbiome, by making dietary changes and taking probiotics, to reduce the negative neurological effects of trauma and adversity, especially early in life. But right now, there’s not enough evidence to draw this conclusion in humans.

For now, the researchers are focused on a larger-scale version of the current study to see if their findings hold up, with results expected later this year.

Steroid Drug Found to Help With Gluten Exposure

In a small study, researchers found that budesonide helped relieve symptoms following accidental gluten exposure.

Taking an extended-release steroid drug may help ease symptoms of gluten exposure in people with celiac disease, according to a new study involving a small series of individual cases.

Published in March 2019 in the journal Clinical Gastroenterology and Hepatology, the study looked at how a handful of patients responded to taking extended-release budesonide, a corticosteroid drug that’s used to treat Crohn’s disease and ulcerative colitis.

Budesonide has previously been found to have beneficial effects in people with recently diagnosed celiac disease who experienced digestive malabsorption. For this study, researchers wanted to know whether it could have benefits if taken after the onset of symptoms following accidental gluten exposure.

The participants included 12 people with biopsy-confirmed celiac disease and one with potential celiac disease. Each was told to take enteric-coated budesonide as soon as possible following the onset of symptoms suggestive of gluten exposure.

Every single participant reported a response to taking the drug, including eight who called the improvement “substantial.” The other options were simply a “response,” or a lesser “partial” response.

In the participants who rated their response as only “partial,” the improvements were mostly related to symptoms outside the digestive system.

While these results are encouraging, the researchers note that steroids shouldn’t be taken lightly as a celiac disease treatment — writing that participants were chosen “because of severe, debilitating gluten reactions due to intermittent inadvertent exposures despite their best attempts to adhere” to a gluten-free diet.

Due to the small and inconsistent nature of this study, the researchers emphasize that its findings are provisional and call for future clinical trials of budesonide for gluten exposure in celiac disease.

Experts Weigh In on Celiac Disease Research and Treatment in 2019

Living with celiac disease, and managing a gluten-free lifestyle, involves navigating a bounty of information and making numerous decisions every day. With all the breathless media coverage of research updates and lifestyle advice, it can be easy to lose track of the big picture when it comes to celiac disease treatment and research.

So we asked three celiac disease experts — two top doctors and the director of the leading advocacy group in the United States — to answer a few questions about where celiac disease management is right now, and where it might be headed. Their responses (condensed and edited for clarity) appear below.

Gluten-Free Living: What have we learned about the causes and biology of celiac disease in recent years? How might these discoveries lead to advances in treatment or prevention?

Alessio Fasano headshotAlessio Fasano, MD, gastroenterologist and director of the Center for Celiac Research and Treatment, Massachusetts General Hospital: For many years, we’ve known a great deal about how people develop celiac disease. We were convinced we really had a grasp of the entire story. The two ingredients that were considered necessary and sufficient were a genetic predisposition, and an environmental trigger that’s mismanaged by the immune system, which is gluten.

What we’ve learned in the last few years is that genetics and environment are absolutely necessary, but not sufficient, to explain who gets celiac disease. We saw things that were at odds with that premise. In identical twins, with identical genes, who ate the same stuff, one twin would develop celiac disease and the other would not in 25 percent of cases. How do you explain that?

In the last 10 to 15 years, we learned that there are three other elements: a gut that leaks, allowing gluten to interact with the immune system; an immune system that’s hyperbelligerent, continuing to fight when it’s not necessary; and a very different microbiome, the ecosystem of the gut, between people with and without celiac disease.

These five elements offer treatment and prevention opportunities that we didn’t have before. Except for genetics, they’re all fair targets to change the destiny of people with celiac disease.

Prevention would be the holy grail, and that’s what we’re looking at in this megastudy called CDGEMM (Celiac Disease, Genomic, Environmental, Microbiome and Metabolomic Study), where we’re following infants since birth when someone in their family has celiac disease. We follow everything about these kids. We’re asking why some take a wrong turn and develop celiac disease, while others do not. What kind of changes happen before the storm is on their doorstep?

Dr. Daniel LefflerDaniel A. Leffler, MD, gastroenterologist and associate professor of medicine, Harvard Medical School: I think our better understanding of celiac disease has allowed us to see that there’s a need for therapies. It’s really more about the clinical picture of the disease, rather than the scientific background.

That being said, I think there are areas where science has helped us attempt to make really safe, targeted therapeutics for celiac disease, even though they’re not really hitting any part of the disease we didn’t know about before.

I think you can group celiac disease therapies into three main groups. One is things that try to detoxify or protect you from gluten. These would be largely glutenase enzymes, but other things have been tried, including gluten binders. Second, there are drugs that prevent gluten from interacting with the immune system in the intestinal wall. And the third category is drugs that try to turn off the abnormal immune response to gluten.

Our improved scientific understanding has suggested ways to target those three parts of the pathogenesis of celiac disease to create an effective therapy, even though we’ve known that those three things are important for a long time.

Marilyn Grunzweig Geller, chief executive officer, Celiac Disease Foundation: As research continues to prove that a gluten-free diet is not a “cure” for celiac disease as was once thought, the case for investing in celiac disease research — both to create new treatments, and to find ways to prevent it — becomes more compelling.

As more physicians learn and accept that patients with celiac disease cannot be written off with “just go on a gluten-free diet”, there should be a corresponding increase in diagnosis with a potential patient base attractive to biopharmaceutical investment to bring therapeutics to market.

GFL: What have we learned about the causes and biology of non-celiac gluten sensitivity in recent years?

Fasano: Not much. We know that besides celiac disease, there are other forms of gluten reactions, which we thought was not the case until the recent past. This includes non-celiac gluten sensitivity.

Some of the steps in the disease process seem to be the same as in celiac disease. You have to be exposed to gluten, it’s only partially digested, there’s gut permeability, and the immune system reacts to it. What comes next is very nebulous for non-celiac gluten sensitivity.

There’s a 30-year difference in science between the two conditions, and that gap can be closed once we have a better understanding of how to define non-celiac gluten sensitivity and what kind of diagnostic tests we can use.

Leffler: Unlike celiac disease, non-celiac gluten sensitivity is just not a well-defined condition. There are no clear biomarkers; there’s no clear genetic marker — yet it’s real. I see it in my patients.

I think the likelihood is that it’s not one disorder. It’s likely a combination of different disorders in different people that lead to significant symptoms when people get exposed to gluten. From a therapeutic perspective, it may be significantly more challenging than celiac disease because we don’t have the same scientific understanding yet.

I think a lot more foundational work has to be done before we get to medications for non-celiac gluten sensitivity.

GFL: What, in your view, are the most promising recent developments in treatments to reduce the effects of gluten exposure in celiac patients?

Fasano: Unfortunately, we have very little for exposure after the fact. If you’re exposed and have symptoms, the only thing you can do is go through the storm and wait for the inflammation to go away.

There are much more promising developments in terms of protection if you find yourself in a situation where the risk of cross-contamination is higher. There are three or four possible pathways that have been explored in clinical trials: drugs for gut permeability, using enzymes to completely digest gluten, blocking the enzyme that activates gluten to be seen by the immune system, and immunosuppressants. These could all help prevent a reaction in cases of cross-contamination, a safety net if you wish.

Leffler: Drug development is such a tricky process that it’s always hard to predict what’s further along. There’s larazotide, which appears to work on some level by preventing gluten entry into the intestine. That should enter a phase 3 trial in the near future, which would clearly make it the front-runner. But it’s the lone drug in its class.

On the other hand, you have things like glutenase enzymes, where there’s a couple of drugs in different phases of development. There’s a lot of experience with those, and a lot of belief that they should be safe and effective, yet none of them is actually in phase 3.

And then there are some of the potentially more transformative types of therapies, ones that try to reset the immune system, that are in phase 2 somewhere. I think you can make an argument for any one of those classes being a front-runner in some regard.

Geller: There are a number of potential celiac disease treatments in the pipeline. While most are in preclinical development or phase 1, ImmusanT is currently in phase 2, Provention Bio and ImmunogenX are heading in to phase 2, and Innovate Biopharmaceuticals [larazotide] is heading into phase 3.

GFL: Gluten-free food options have grown enormously in recent years, supported by many people without celiac disease adopting gluten-free and reduced-gluten diets. Do you think this development has led to improved quality of life for people with celiac disease?

Fasano: I can tell you that there have been a lot of positive outcomes from this gluten-free frenzy, but of course they come at a price. Twenty years ago, if you were a celiac, you had to go to the special health-food store. Your options were limited to three or four items whose palatability was questionable, with the prices astronomically high.

Now you have a wealth of products everywhere, very palatable, much more affordable. That was simply unimaginable before. But people who are very careful, and people who are reckless, have jumped on this business opportunity.

Imagine if you go to a restaurant as a celiac and say you have to go gluten-free because you have a condition, and a half hour before, they’ve served someone who said, “I want a gluten-free menu, and bring me a beer.” This fuels the sense of a fad diet, and people may take this very lightly and not use the proper stringency in serving you.

Leffler: I think it’s been a net positive for sure. Having celiac disease today is much more manageable on some level than it was 10 or 20 years ago. The costs of gluten-free foods haven’t really dropped much, but certainly the variety and availability have increased, and the quality has probably increased.

At the same time, we know that it has also led to sort of an erosion of a feeling of the seriousness of the condition. You go to restaurants and see people order gluten-free, but then still have bites of their roll. It leads to a lot of confusion.

And it hasn’t addressed what’s in many ways the biggest issue for people with celiac disease, which is these small cross-contamination gluten exposures in restaurants. Yes, it’s easier to go the supermarket and go shopping for tasty foods. But I’m not sure that’s made the celiac community healthier. We still see a lot of people for whom these small, unavoidable contaminations are leading to ongoing symptoms and an inability to control their celiac disease well.

Geller: Mostly yes. Certainly the availability of gluten-free foods in the market, and the FDA labeling rule for these products, have been life-changing for people with celiac disease. In 2009, I was ordering gluten-free bread from Colorado and paying exorbitant shipping fees just so my son could have sandwiches that looked similar to his classmates’. Dining out was more difficult then too, as no restaurant offered gluten-free options on their menu.

However, because of the gluten-free fad, we have seen a backlash in the public’s and restaurant servers’ acceptance of the seriousness of celiac disease — what can be so hard about eating gluten-free if everyone is? And when you dig deeper and ask questions about those gluten-free options, it turns out that while the meal may have been prepared without gluten-containing ingredients, that meal has been contaminated through cross-contact in many ways.

So while quality of life has improved due to greater choice of foods and better opportunities to dine out, most people with celiac disease still face daily the stress of accidentally ingesting gluten and all of the horrible symptoms that follow.

GFL: How do you guide celiac patients to adopt the proper precautions to avoid gluten exposure, without those precautions going too far?

Fasano: There are two breeds of patient that come to our clinic. One is those who don’t really appreciate the importance of a gluten-free diet, who think that once in a while, you can make an exception. Much more common is the attitude of putting yourself in a bubble, being so paranoid that you don’t live a life anymore. They don’t travel anymore, they don’t go out, they don’t let their kids go to camp or sleepovers.

Both attitudes are inappropriate. Ultimately, we’re trying to implement a treatment that preserves the patient’s quality of life. Once you have learned the do’s and don’ts, and you know how to navigate a gluten-free diet, the intent is that you lead a normal life. That’s what we communicate to patients. Ultimately, if everything works well, you won’t be distinguishable from anyone else. Your symptoms are gone, your autoantibodies are gone, your intestinal biopsy shows that it’s healed. And if you don’t tell me that you’re a celiac, I can’t tell.

Leffler: I have that conversation quite frequently with all my patients. We want to strike that balance between being adequately vigilant, but not neurotic. In the end, we want people to have a good quality of life. It’s not a net gain to be miserable but have great control of your celiac disease.

Unfortunately, one of the issues is that because we don’t have great tools for assessment and monitoring, we treat a gluten-free diet as a one-size-fits-all therapy, where we tell everyone to be as strict as possible — even though we know that some people can probably do fine with small amounts of gluten exposure. We just don’t know who they are. And some people, no matter how strict they are, will probably never be able to get full disease control.

This is one reason why I think there’s a real need for celiac disease monitoring and follow-up. For example, we tell people to try eating oats and see how they do. I worry about people who over-restrict, in some ways, just as much as I worry about people who aren’t careful enough.

Geller: Label reading and asking questions are your two best tools in avoiding gluten exposure. If you’re sharing a kitchen with others who do not eat gluten-free, use your own toaster, cutting board, colander, and cleaning sponges, and do not share condiments that have been exposed to gluten. For social events, offer to bring a gluten-free dish if you’re not sure the host understands how to avoid cross-contact with gluten.

And my personal advice is what I call the pre-eat and post-eat. If you don’t think you’ll be able to eat safely at an event, and cannot bring your own food or snacks, make sure to eat a substantial gluten-free meal before and then again after the event if you’re still hungry. While it may feel unfair that you cannot enjoy the food at an event, there’s no need to punish yourself by going without food altogether. In fact, one of my son’s favorite memories is our In-N-Out Burger post-party runs — protein-style, of course.